Age is the major risk factor for neurodegenerative diseases. As society age's neurodegeneration become increasingly common, yet the molecular and cellular mechanisms underlying this complex condition remain largely unknown. The goal of this proposal is to explore novel avenues to investigate mechanisms of neurodegeneration in an unbiased manner. A misexpression screen that takes advantage of the power of Drosophila genetics is used to identify genes that may be involved in late-onset behavioral defects (aging). Novel genes that are thus identified to be involved in late neuronal dysfunction can be then characterized and validated in the Drosophila central nervous system by combining genetics, imaging and behavior. Effects of altered gene function can also be tested and validated in the mouse brain, by retrovirus-mediated expression in neurons of the young adult and aging brain. Cell-autonomous effects emerging from these studies will largely contribute to understanding the specific aspects of neuronal function that are affected by the candidate gene. In parallel, a transgenic mouse model will be built based upon the gene identified in Drosophila. Altered gene function in the mouse brain will serve as a tool to characterize the effects on neuronal networks and, ultimately, on brain function, from simple locomotor behaviors to complex learning traits. In addition, transgenic mice should in the future be amenable to high throughput chemical/ small molecule library screens to identify drugs interfering with the degenerative process. A particular gene that emerged from the fly screen, enabled, has been selected as a proof of principle for the approach. The success of the proposed project relies on building a close interaction among two laboratories at the Leloir Institute (Buenos Aires) and a laboratory at Childrens Hospital, Harvard Medical School. Graduate students, postdoctoral fellows and young investigators will have the opportunity to obtain training at Harvard to generate, characterize and maintain transgenic mice. This know-how will certainly improve the capabilities to develop novel models of neurodegeneration at the foreign institution. The ultimate goal is to establish a long-term collaboration in order to bring our local scientific community in closer contact with novel technologies for research on this challenging topic. To accomplish such goal the preparation of full RO1 research proposal is warranted. PUBLIC HEALTH RELEVANCE: Age is a major risk factor for neurodegenerative diseases, which cause a terrible human toll. As society ages, neurodegenerative diseases will become increasingly common, underscoring the need for an in depth understanding of the molecular mechanisms underlying these devastating diseases, as well as the development of specific treatments.